Patients with severe illnesses resulting from such diverse causes as trauma, infection, burn injury, major surgery, and certain cancers frequently develop a catabolic response that contributes to disease morbidity and complications, delays recovery, and may affect final disease outcome. Intensive nutrition support has significant benefit in catabolic patients, but current methods of nutrition support often do not reverse the catabolic state. In these patients, resistance to the actions of anabolic hormones, including growth hormone, appears to be a significant factor contributing to the catabolic response. The long-term objectives of this project are to define the molecular mechanisms that lead to growth hormone resistance during severe illness and, ultimately, use this information to develop more effective strategies for managing critically ill patients. During the previous grant period, specific signaling defects in the growth hormone pathway in the liver were shown to develop in rats in an experimental catabolic state induced by injection of endotoxin. Subsequent studies demonstrated that growth hormone resistance correlated with a marked increase in mRNAs for several of the recently described negative-regulatory SOCS (suppresser of cytokine signaling) genes. This has led to the hypothesis that cytokines elaborated in response to endotoxin activate SOCS genes as part of a negative feedback loop and, through a specificity- spillover mechanism, the SOCS proteins then inhibit growth hormone signaling. Additional studies have shown that SOCS mRNAs are increased by fasting or protein malnutrition, consistent with a role for these proteins in malnutrition-induced growth hormone resistance. The specific goals of this project are: (1) to define the extent and mechanisms of nutritional regulation of SOCS genes in rat liver and skeletal muscle, (2) to investigate the functional effects of SOCS proteins on GH signaling in liver tissue in vivo using recombinant adenovirus-mediated gene transfer, (3) to investigate the synergistic effects of malnutrition and endotoxin in the induction of SOCS genes, and (4) to examine the effects of the tyrosine phosphorylation modifying agent vanadyl sulfate as a potential pharmacological approach to decreasing growth hormone resistance. The work will investigate fundamental molecular mechanisms of the catabolic response in pathophysiologically relevant ecperimental models with the ultimate objective of developing new approaches to the use of nutritional, hormonal, and pharmacological interventions in the treatment of catabolic patients.